ChronicinfectionwithhepatitisBvirus(HBV)afflicts~400millionpeopleworldwide,including1.5-2millionin theU.S.A.ChronichepatitisB(CHB)leadstoearlydeathfromcirrhosis,liverfailureandprimarylivercancer (HCC) in at least 1 million people annually. Current antiviral therapies (AVT) can suppress but rarely cure infection,emphasizingneedforfreshapproaches.Weproposeonehere. MostCHBpatientsreceivingAVTintheWesthave?earlyantigennegative(HBeAg-)?disease,causedbya futilehostimmuneresponseagainstamutatedformofHBV.Thecurrentstandard-of-careislifelongAVTwhich canpreventdiseaseadvancementandlikelylowerHCCrisk.However,indefiniteAVTincursfinancialburdento healthcaresystemsandpatients,raisessafetyconcernsandcarriesdrugresistancerisk. Newdatafrom33HBeAg?CHBpatientsinGreece,supportedbyourpilotstudy,suggestthatAVTwithdrawal after ?3.7 years (192 weeks) of viral suppression can be safe, benefit many and even stimulate protective immunity.Duringfollow-up,18(55%)achievedsustainedviralandbiochemicalresponses.Ofthese,13(39%of the original cohort) went on to clear HBV by generating neutralizing surface antibody (HBsAb). This seismic resultindicatedthatinHBeAg-CHB,AVTwithdrawalislikelysafeandcaneffect?closetocure?ofwhatwould otherwisebealifelong,life-threateningandindefinitelytreatedinfection.Seminally,italsoopensanewdoorfor understandinghowtotiltacurativehostimmuneresponseinCHB,whichwealreadystudy. Inthisgrant,weproposetestingthefindingsoftheGreekstudyinalarger,ethnicallydiverseSanFrancisco populationthatisnaturallyenrichedforAsianswhocomprisetheworld?sgreatestHBVreservoir.Inparallel,we willusecellularandmolecularstudiesonliverandbloodfromthepatientstodissectimmunologicalmechanisms ofseroclearanceversuspersistenceofHBVanditsantigens.Thetranslationalscientificcomponentwillinpart bedrivenbyhypothesesbasedonourpublishedandunpublisheddata;?anditwillalsocontainahostgenetic prospectingarmthatwillseekevidenceforsignaturegeneexpressionpatternsthatbothpredictoutcomeand couldpointtounsuspectedmechanismsofimmunity.Akeyobjectivewillbetoattempttodistinguishpatients whoaremostorleastlikelytobenefitfromthetreatmentwithdrawalintervention. METHODS: An IRB-approved, 2-center (CPMC & UCSF) multidisciplinary prospective study of clinical outcomes,geneticprofilesandimmuneresponsesin80adulthumanpatientswithHBeAg-CHB,duringandafter oralAVT,usingserialbloodsamplesandliverbiopsytissue.30adultHBeAg-controlswillalsobestudied. PATIENT OUTCOMES (PROJECTED) 31 patients are predicted to HBsAb seroconvert and clear circulating HBVDNAandantigens;?49arepredictedtoremaininfected:36withactive,and13withquiescent,CHB.Akey goalistodeterminewhichHBeAg-CHBpatientscansafelystopAVTandbenefit.Thisstudycouldhavemajor therapeutic,managementandhealth-carecostimplications. 1